The present invention relates to a method for the treatment of pertussis.
Despite the availability of a highly effective vaccine, whooping cough (pertussis) remains a global problem and a persistent clinical challenge. Fears about vaccine safety have spawned recent epidemics in industrialized nations like Japan, Great Britain, and Sweden; even in the U.S., with vaccine acceptance approaching 95%, new estimates of the annual number of pertussis cases are as high as 125,000 (Sutter et al., JAMA 26-7, 386-391 (1992).]Much of pertussis research has centered on the development of an acellular vaccine with a lower side effect rate, but it is unlikely that the pertussis burden in well-vaccinated countries will decrease. Infants and children hospitalized with pertussis still must endure frequent violent coughing episodes that continue for weeks after antibiotics have eliminated the bacteria. Complications range from the encephalopathy (presumably from anoxia) to secondary pneumonia, the latter being the most frequent cause of pertussis-related mortality [Olson, Medicine 54, 427-469 (1975)]. Currently, there is no therapy to relieve the debilitating symptoms of pertussis, shorten its duration, or reduce the frequency of sequelae.
The causative agent of pertussis is Bordetella pertussis (and, less frequently, B. parapertussis), which specifically colonizes and then destroys the ciliated cells lining the large airways [Mallory et al., J. Med. Res. 27, 115-123 (1912)]. The consequences of this cytopathology are severe, since ciliary activity is normally the sole means of transporting mucus out of the respiratory tract. As mucus, multiplying bacteria, and inflammatory debris accumulate, coughing becomes the only remaining means of airway clearance.
Of the various toxins and virulence-related factors produced by B. pertussis, only one has been demonstrated to reproduce the specific respiratory tract cytopathology of the pertussis syndrome. That molecule is tracheal cytotoxin (TCT), a low molecular weight glycopeptide released by B. pertussis during normal growth.
It is known that the destruction of ciliated cells can be duplicated by TCT (Goldman et al., Infect. Immun. 36, 782-794 (1982)], and this toxin has been subsequently purified [Cookson et al., Infect. Immun. 57, 2223-2229 (1989)] and chemically characterized [Cookson et al., Biochemistry 28, 1744-1749 (1989)]. TCT is enzymatically processed from B. pertussis cell wall peptidoglycan and accumulates at micromolar levels in the culture supernatant during log-phase growth. It is a 921 dalton disaccharide-tetrapeptide and is illustrated in the accompanying FIG. 1.